Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Diabetes mellitus is characterised by an abnormality of carbohydrate metabolism resulting in elevated glucose levels in both the blood and the urine. The failure of the human body to properly metabolise the glucose is caused by defects in insulin secretion or use of insulin. Insulin is produced by β-cells in the islets of the pancreas and permits the body to utilise glucose as a source of energy. When this process cannot occur, the body compensates by utilising alternative sources of energy such as stored fats. However, this leads to rapidly rising levels of glucose and the accumulation of ketones in the bloodstream due to the occurrence of extensive fat metabolism.
Diabetes is broadly classified into two groups termed Type 1 diabetes and Type 2 diabetes. Type 1 diabetes (often referred to as juvenile onset diabetes due to its appearance in childhood or early adolescence) is a debilitating autoimmune condition caused by the selective destruction of insulin producing β-cells in the islets of the pancreas. Its onset is abrupt and occurs typically prior to the age of 20 years. Presently, however, Type 1 diabetes is increasingly presenting in adults. This disease is characterised by lack of β-cell function and no insulin production, and therefore insulin therapy is required. Type 2 diabetes, however, is characterised by insulin resistance, a condition in which the body fails to properly use insulin, which is often accompanied by obesity and other metabolic disorders. There are frequently no overt symptoms observed. Insulin secretory defects are evident very early in disease in both Type 1 and Type 2 diabetes, despite their differing aetiology.
In the absence of treatment, diabetes can be fatal while poorly controlled diabetes leads to the appearance of complications such as diabetic glomerulosclerosis, wherein the kidneys are irreversibly damaged leading to renal failure. Treatment of type 1 diabetes and also severe symptoms of type 2 diabetes is generally by daily insulin injection to replace the insulin which the damaged β cells are no longer able to produce. However, even in the face of an optimised treatment regime of this type, complications and side effects are common. For example, diabetic vascular complications, affecting both micro- and macro-blood vessels, represent major causes of disability and death in the patients with type 1 and type 2 diabetes. In fact, diabetes is now recognized as a potent and independent risk factor for the development of coronary, cerebrovascular and peripheral atherosclerotic disease (Beckman et al., 2002, JAMA 287:2570-2581).
Treatment of diabetes can also be effected via the transplantation of insulin-secreting tissue. However, since this latter strategy relies on the use of scarce human tissue as a source, it seems unlikely that there will ever be sufficient numbers of organs available to assist more than a selected number of insulin-dependent diabetics. Furthermore, these patients would have to undergo a long term regimen of immunosuppressive drugs.
Accordingly, there is an ongoing need to develop alternative and more effective methods of regulating glucose levels in diabetic patients. In work leading up to the present invention, a population of cells have been generated which synthesise, store and secrete insulin in response to glucose stimulation. However, whereas existing cell lines of this type have secreted insulin in a highly sensitive manner, and therefore in response to even very low glucose levels, the genetic modification introduced into the cells of the present invention has refined their glucose responsiveness such that insulin is produced only in response to physiologically relevant levels of glucose, that is, levels equal to or greater than the minimum levels of glucose which would result in pancreatic β cell insulin production in normal individuals.